9-33246620-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014471.3(SPINK4):c.107T>G(p.Ile36Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,078 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 31)
• Consequence: SPINK4 NM_014471.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16

Genes affected

SPINK4 (HGNC:16646): (serine peptidase inhibitor Kazal type 4) Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity and response to xenobiotic stimulus. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK4	NM_014471.3	c.107T>G	p.Ile36Ser	missense_variant	3/4	ENST00000379721.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK4	ENST00000379721.4	c.107T>G	p.Ile36Ser	missense_variant	3/4	1	NM_014471.3	P1
SPINK4	ENST00000379725.5	c.176T>G	p.Ile59Ser	missense_variant	4/5	3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152078 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152078 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74290

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

The c.107T>G (p.I36S) alteration is located in exon 3 (coding exon 3) of the SPINK4 gene. This alteration results from a T to G substitution at nucleotide position 107, causing the isoleucine (I) at amino acid position 36 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0064	T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.97	N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.58	N;N
REVEL	Benign	0.15
Sift	Benign	0.28	T;T
Sift4G	Benign	0.49	T;T
Polyphen		0.30	.;B
Vest4		0.59
MutPred		0.41		.;Gain of disorder (P = 5e-04);
MVP		0.68
MPC		0.33
ClinPred		0.92	D
GERP RS		2.3
Varity_R		0.087
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1310963689; hg19: chr9-33246618;